Drug Induced Liver Injury and Stevens Johnson Syndrome

SJS Symposium NIH, Bethesda, MD

March 3-4, 2015

Jay H. Hoofnagle, M.D. Liver Disease Research Branch, NIDDK

Drug-Induced Liver Injury • ~3-10% of acute liver injury in the US • Single, major cause of acute liver failure • Common cause for a medication to be

abandoned during development • Common cause for withdrawal or restriction of

use of an approved medication • Frequently accompanies Stevens Johnson

syndrome

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Etiology of Acute Liver Failure in the US Adult Registry (n = 2,102)

ALF Study Group, Jan 2014 46%

11% 12%

Drug-Induced Liver Injury • Two major forms: direct & idiosyncratic

• Direct: intrinsically hepatotoxic agent; injury is frequent (1-100%), dose-related, reproducible in animal models, “expected”

• Idiosyncratic: not inherently hepatoxic, rare (1:1,000-1:1,000,000), not dose related, not reproducible in animals, “unexpected”

March 2015

Idiosyncratic Hepatotoxicity

Unexpected outcome, not dose-related, rare Isoniazid (~1:500) Amoxicillin/Clavulanic acid (~1:2,500) Diclofenac (~1:30,000)

Idiosyncrasy: immunologic or metabolic

Phenotypes: acute hepatitis, Hepatocellular, Cholestatic or “Mixed”

Etiology, generally unknown

March 2015

Idiosyncratic Drug-Induced Liver Injury: Immunoallergic hepatitis

Acute liver injury with Rash, fever, facial edema, lymphadenopathy, Eosinophilia, atypical lymphocytosis

Typically short latency, 1-30 days Rash and fever may precede hepatic

manifestations Injury is usually hepatocellular initially, but

may evolve into a cholestatic pattern

March 2015

Idiosyncratic Drug-Induced Liver Injury: Immunoallergic hepatitis: many names

Hepatitis with simple drug rash Immunoallergic hepatitis Drug-induced hypersensitivity syndrome Anticonvulsant hypersensitivity syndrome DRESS Stevens Johnson syndrome Toxic epidermal necrolysis (TEN)

March 2015

Drug-Induced Liver Injury & SJS

Have a lot in common Severe adverse events Rare Idiosyncratic, unexpected Sometimes overlap Clinical and Research Challenge

March 2015

Drug-Induced Liver Injury: Mechanisms and Test Systems: NIH Research Symposium: October 17-18, 2000

Drug-Induced Liver Injury Network

• Created in 2003, Cooperative Agreement [NIDDK] • Consortium of 5-8 Clinical Centers • Data Coordinating Center • Sample Repository, Genetics Core • Aim: Collect and fully characterize cases of

clinically apparent, drug-induced liver injury (phenotype) to allow for mechanistic studies into its etiology and potential prevention or treatment.

DILIN 2015

CPMC Davern

U N Carolina Watkins

U Penn/ Einstein Reddy / Navarro

U Michigan Fontana

Indiana U Chalasani

USC/ UCLA Stolz/ Durazo

UTSW Lee

Mayo Talwalkar

Duke CRI Barnhart

Mt Sinai Odin

U Conn Bonkovsky

Previous site

Current site

Prospective Study Enrollment Target: 2 patients/ center/ month

N=932 N=932 N=932

08/28/2013

N = 1434

Causality in Drug Induced Liver Injury

March 2015

DILI is a diagnosis of exclusion

Compatible history

Negative tests for hepatitis A, B, C and E

Absence of alcoholism, shock, autoimmunity

Imaging studies of liver and biliary tree

Known cause and compatible signature

No specific tests to prove causality

Drug-Induced Liver Injury Causality Assessment

March 2015

Score Causality Percent Legal Description

1 Definite ≥95% Beyond a reasonable doubt

2 Very Likely 75-94% Clear and convincing

3 Probable 50-74% Preponderance of the evidence

4 Possible 25-49%

5 Unlikely <25%

Each case is reviewed and scored by 3 DILIN hepatologists independently; discordances are resolved by email or telephone discussions.

Yes

No

DILIN: First 1,068 Cases

899 were adjudicated as definite, highly likely or probable (83%) Caused by ~250 different agents Prescription drugs: 84% Herbals and Dietary Supplements: 16% Top 10 most common: 36% Top 25 most common: 50%

Chalasani et al Gastro 2015, in press

13% possible, 5% unlikely

Prescription Drug-Induced Liver Injury Twenty most common causes

Rank Agent No Rank Agent No

1 Augmentin 91 11 Phenytoin 12

2 Isoniazid 48 12 Methyldopa 11

3 Nitrofurantoin 42 13 Azathioprine 10

4 TMP/SMZ 31 14 Hydralazine 9

5 Minocycline 28 15 Lamotrigine 9

6 Cefazolin 20 16 Mercaptopurine 9

7 Azithromycin 18 17 Atorvastatin 8

8 Ciprofloxacin 16 18 Moxifloxacin 8

9 Diclofenac 15 19 Allopurinol 7

10 Levofloxacin 13 20 Amoxicillin 7

Chalasani et al: in press 2015

Drug-Induced Liver Injury 9 Cases of Stevens Johnson Syndrome

No Agent SJS Jaundice Fatal

1 Lamotrigine EM vs SJS Yes No

2 Lamotrigine DRESS vs SJS Yes Yes*

3 Lamotrigine SJS No No

4 Azithromycin SJS Yes Yes

5 Azithromycin TEN Yes No

6 Carbamazepine SJS/TEN Yes Yes

7 Moxifloxacin SJS Yes No

8 Diclofenac SJS/TEN Yes Yes

9 Nitrofurantoin SJS Yes No

All 89% 44%

* Death from hepatic failure

Drug-Induced Liver Injury and SJS Feature SJS Cases

(9) All DILI Cases

(899) Mean age 32 years 49 years

Sex (female) 78% 59%

Race: White African American Asian American

44% 33% 22%

79% 12% 7%

Median time to onset 14 days (1-58) 36 days (1 day-10 yrs)

Jaundice 89% 70%

Fatal 44% 11%*

Liver Transplantation in 4%

Drug-Induced Liver Injury & SJS Feature Chalasani et al

Indianapolis, US 2004-2012 (n=899)

Devarbhavi et al India, Bangelore

1997-2013 (n=670) SJS/TEN 9 (1%) 32 (5%) Mean age 32 years 31 years Female sex 78% 56% Jaundice 89% 62% Latency 3-58 days < 60 days Drugs Lamotrigine (3) Phenytoin (8)

Azithromycin (2) Dapsone (4) Carbamazepine (1) Carbamazepine (4)

Moxifloxacin (1) SMZ/TMP (3) Diclofenac (1) Nevirapine (3)

Nitrofurantoin (1) Allopurinol (2)

Lamotrigine

Accounted for 12 of the 899 cases of DILI 11 had DRESS (7), SJS (3) or drug rash (1) Median age, 26 years; 75% women 63% white, 25% Afr Am, 13% Asian Median latency 23 days (8-117 days) Jaundice 83% Fatality 8%

March 2015

Spectrum of Drug Induced Liver Injury

Severe clinically apparent cases represent the “tip of the iceberg”

Acute Liver Failure

Liver Injury with Jaundice

Symptomatic Liver injury without Jaundice

Asymptomatic rise in Serum Enzymes

Spectrum of Drug Hypersensitivity Syndromes

Perhaps SJS & TEN represent the “tip of the iceberg”

SJS/TEN

DRESS

Drug Rash

Hypersensitivity without symptoms (Eosinophilia)

Drug Fever

Immunoallergic injury

Drug-Included Liver Injury & SJS

The 9 patients with SJS were often exposed to multiple other medications some of which have been implicated in SJS

Number of other agents, 0-14, mean = 5 Anticonvulsants: clonazepam, levetiracetamin, phenytoin,

pregabalin, valproate Analgesics: acetaminophen, ibuprofen, meloxicam Antibiotics: cephalosporins, clindamycin, doxycycline,

erythromycin, fluoroquinolones, penicillin, piperacillin Psychotrophic: alprazolam, amitryptyline, aripiprazole,

escitalopram, fluoxetine, lithium, lorazepam, methylphenidate, quetiapine, trazodone, ziprasidone

March 2015

LiverTox Drug Sections (~750 currently)

• Overview of the drug (1-2 pages) Background Hepatotoxicity Mechanism of Injury Outcome and Management

• Representative cases • Liver Histology • Chemical structure • Link to Product label (package insert) • Annotated references with links

March 2015

Diclofenac in LiverTox

LiverTox Status: 2015

Official release: October 2012 Current web activity: 115,000 unique

visitors per month 750 agents described 1.3 million words 13,000 annotated references 1,000 clinical cases

March 2015